PHLDA2 (Pleckstrin homology-like domain, family A, member 2)

	Figure 1. Schematic representation of the modular structure of the PHLDA2 protein. The PHLDA2 protein structure consists of a single PHL domain (pleckstrin homology-like) from amino acid residues 7 to 99, flanked by short terminal extensions.
Description	The protein encoded by the PHLDA2 gene consists of 152 amino acids, a molecular weight of 17.1 kDa, composed mainly of the PHL domain (93aa) (Frank et al., 1999). The PHL domain present in its structure has a moderate binding affinity to phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate (PIP3) (Frank et al., 2002; Saxena et al., 2002). NP_003302.1 (https://www.ncbi.nlm.nih.gov/protein/NP_003302)
Expression	According to the integrative human mRNA and protein expression map, the PHLDA2 is remarkably expressed in placental tissue. Tissues of stomach, colon, prostate, duodenum, small intestine, and kidney are those of more abundant expression (Fagerberg et al., 2013). A monoallelic expression is observed in human fetal tissues such as the kidney, intestine, liver, heart, being the maternal allele preferentially expressed (Lee & Feinberg, 1998). It has been shown that PHLDA2 expression is down-regulated under hypoxia in human trophoblasts (Roh et al., 2005). PHLDA2 has been described as the first apoptotic related gene regulated by genomic imprinting (Lee & Feinberg, 1998). PHLDA2 expression is negatively regulated at the minimum by two different mechanisms, one by at least to miRNAs ( MIR214 MIR148A-5p) and by a methyltransferase called EZH2 (Lv et al., 2015; Idishi et al., 2018; Li et al., 2019).
Localisation	The mature PHLDA2 protein subcellular localization is at the cytoplasm, cellular membrane, and also peripheral membrane protein (https://www.uniprot.org/uniprot/Q53GA4).
Function	The PHLDA2 gene is one of several genes clustered at 11p15.5 domain, an important region for tumor suppressor genes. Changes in this chromosomal region have already been described in Beckwith-Wiedemann syndrome, hydatidiform mole, and different types of tumors (Hu et al., 1997, Weksberg et al., 2005, Feinberg, 1999). The protein encoded by the PHLDA2 gene can play different biological roles depending on cell or tissue specificity (https://www.uniprot.org/uniprot/Q53GA4). In mouse models, PHLDA2 negatively controls glycogen storage during pregnancy, negatively regulates the expression of a variety of placental hormones through the spongiotrophoblast layer (Tunster et al., 2010; Tunster et al., 2016). PHLDA2 (TSSC3) has been shown to induce apoptosis by increasing the intrinsic pro-apoptotic pathway members such as BAK1, BCL2L11 (BIM), CYCS (Cyt c), and the BAX: BCL2 ratio and downregulating anti-apoptotic proteins like BCL2 and FAS in human osteosarcoma cell lines (Dai et al., 2012; Huang et al., 2012). PHLDA2 has also been shown to have a role in anoikis resistance and metastasis through the interaction with RANBP9 and downregulation of the SRC -dependent Akt pathway in osteosarcoma cells (Dai et al., 2016). Experimental evidence also associated increased expression of PHLDA2 in trophoblast cells with cell-cycle inhibition through the reduction of cyclin D1 and cyclin E ( CCND1 and CCNE1) arresting cells in G0/G1 phase of the cell cycle (Jin et al., 2015). PHLDA2 increases epithelial-mesenchymal transition (EMT) of osteosarcoma cells by upregulating mesenchymal markers, such as CDH2 (N-cadherin), VIM (Vimentin), and SNAI1 (SNAIL), and inhibiting the epithelial markers like CDH1 (E-cadherin) (Dai et al., 2016, Lv et al., 2016). Additionally, PHLDA2 can inhibit Src/Akt pathway suppressing self-renewal in osteosarcoma stem cells (Yan et al., 2017), and this Src/Akt pathway inactivation prevents MTOR phosphorylation, that drives osteosarcoma cells to autophagy, contributing to the inhibition of tumorigenesis and metastasis (Zhao et al., 2018).
	Figure 2 - Schematic diagram of the modulators, effectors, and biological processes associated with PHLDA2 expression. Different stimuli can modulate PHLDA2 expression. Therefore, various biological processes are associated depending on the stimulus and cellular effectors.
Homology	The human protein encoded by the PHLDA2 gene is highly conserved in vertebrates. Orthologs have been described in Pan troglodytes (chimpanzee); Macaca mulatta (Rhesus monkey); Bos taurus (cattle); Mus musculus (house mouse); Rattus norvegicus (Norway rat); Gallus gallus (chicken), Xenopus tropicalis (tropical clawed frog), Danio rerio (zebrafish) (https://www.ncbi.nlm.nih.gov/homologene/2482), among others also described at Ensembl genome browser (https://www.ensembl.org/ PHLDA2 ENSG00000181649, Ensembl release 100 - April 2020). Moreover, two protein paralogues are known: PHLDA1 (pleckstrin homology like domain, family A, member 1) e PHLDA3 (pleckstrin homology like domain, family A, member 3) (https://www.ensembl.org/ PHLDA2 ENSG00000181649)

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